EP1175155A4 - Procede destine a reduire la predisposition a la formation de tumeurs provoquees par la 3-desoxyglucosone et les precurseurs de cette substance - Google Patents

Procede destine a reduire la predisposition a la formation de tumeurs provoquees par la 3-desoxyglucosone et les precurseurs de cette substance

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Publication number
EP1175155A4
EP1175155A4 EP00923361A EP00923361A EP1175155A4 EP 1175155 A4 EP1175155 A4 EP 1175155A4 EP 00923361 A EP00923361 A EP 00923361A EP 00923361 A EP00923361 A EP 00923361A EP 1175155 A4 EP1175155 A4 EP 1175155A4
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European Patent Office
Prior art keywords
group
glycated
lysine
amino
precursor
Prior art date
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Application number
EP00923361A
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German (de)
English (en)
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EP1175155A1 (fr
Inventor
Truman R Brown
Francis Kappler
Steven H Seeholzer
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Fox Chase Cancer Center
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Fox Chase Cancer Center
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Publication of EP1175155A1 publication Critical patent/EP1175155A1/fr
Publication of EP1175155A4 publication Critical patent/EP1175155A4/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a new therapeutic use of various known classes of compounds that have the ability to complex or otherwise bind to reactive carbonyl moieties of compounds formed from the cleavage of early stage glycosylation products. These compounds have been reported to be effective for treatment of various disease states, including retinopathy, cataracts, diabetic kidney disease, glomerulosclerosis, peripheral vascular disease, arteriosclerosis obliterans, peripheral neuropathy, stroke, hypertension, atherosclerosis, osteoarthritis, periarticular rigidity, loss of elasticity and wrinkling of skin, stiffening of joints, and glomerulonephritis. More specifically, it has now been discovered that the compounds described hereinbelow, because of their effectiveness in binding such reactive carbonyl-containing compounds, are also useful in reducing a susceptibility to tumor formation, as well as in preventing or delaying the onset of tumor formation.
  • compositions described in these patents comprise various active agents which have in common the capability of inhibiting the formation of advanced glycosylation end products (AGEs) of target proteins by reacting with carbonyl compounds, such as glycoaldehyde, glyceraldehyde or 3-deoxyglucosone, formed from the cleavage of Amadori or other "early glycosylation product(s)", as defined in those patents.
  • AGEs advanced glycosylation end products
  • A717 which is produced by cell line ATCC HB 9596.
  • Another antibody useful for this purpose is one which reacts immunospecifically with an epitope comprising N-deoxyfructosyllysine, which is present in glycated LDL, but not in unglycated LDL or in other glycated or unglycated plasma proteins, the epitope being present in apolipoprotein B of glycated LDL.
  • U.S. Patent 4,761,368 issued to A. Cerami describes the isolation and purification of a chromophore present in browned polypeptides, e.g., bovine serum albumin and poly-L-lysine.
  • the chromophore, 2-(2-furoyl)-4(5)-2(furoyl)- lH-imidazole (FFI) is a conjugated heterocycle derived from the condensation of two molecules of glucose with two lysine-derived amino groups.
  • This patent further describes the use of FFI in a method for measuring "aging” (the degree of advanced glycosylation) in a protein sample wherein the sample “age” is determined by measuring the amount of the above-described chromophore in the sample and then comparing this measurement to a standard (a protein sample having an amount of FFI which has been correlated to the "age" of the sample).
  • aging the degree of advanced glycosylation
  • the present invention arose, in part, from the discovery of a metabolic pathway that involves the enzyme-mediated conversion of fructose lysine (FL) to fructose-lysine-3 -phosphate (FL3P) and produces relatively high concentrations of 3-deoxyglucosone (3DG) in organs affected by diabetes.
  • FL fructose lysine
  • FL3P fructose-lysine-3 -phosphate
  • 3DG 3-deoxyglucosone
  • a method of reducing a suceptibility to tumor formation induced by the presence of 3DG in a subject by administering to the subject at least one of the therapeutic agents identified below in the detailed description of the invention is provided. Also in accordance with the present invention a method is provided for preventing or delaying the onset of tumor formation caused by 3DG. The method comprises administering a therapeutic amount of an agent that counteracts the deleterious effects of 3DG that contribute to tumor formation.
  • this invention provides a method of making high fructose corn syrup less likely to induce tumor formation, by treating 3DG-containing high fructose corn syrup to reduce the 3DG levels thereof to below the normal level of 3DG present in human plasma, which is in the range from about 50 to about 100 nM.
  • the resultant high fructose corn syrup has a 3DG content of less than 0J ⁇ M.
  • FIGURE 1 illustrates the reactions involved in the lysine recovery pathway.
  • Glycated-Lysine Residues refers to the modified lysine residue of a stable adduct produced by the reaction of a reducing sugar and a lysine-containing protein.
  • lysine residues on proteins which come in contact with serum, or other biological fluids, can freely react with sugar molecules in solution. This reaction occurs in multiple stages. The initial stage involves the formation of a Schiff base between the lysine free amino group and the sugar keto-group. This initial product then undergoes the Amadori rearrangement, to produce a stable ketoamine compound. This series of reactions can occur with various sugars. When the sugar involved is glucose, the initial Schiff base product will involve imine formation between the aldehyde moiety on C-l of the glucose and the lysine e-amino group.
  • glycated-lysine residue glycated protein and glycosylated protein or lysine residue are used interchangeably herein, which is consistent with current usage in scientific journals where such expressions are often used interchangeably.
  • Fructose-lysine The term "fructose-lysine" (FL) is used herein to signify any glycated-lysine, whether inco ⁇ orated in a protein/peptide or released from a protein/peptide by proteolytic digestion. This term is specifically not limited to the chemical structure commonly referred to as fructose-lysine, which is reported to form from the reaction of protein lysine residues and glucose. As noted above, lysine amino groups can react with a wide variety of sugars. Indeed, one report indicates that glucose is the least reactive sugar out of a group of sixteen (16) different sugars tested (Bunn et al., Science, 213: 222 (1981)).
  • tagatose-lysine formed from galactose and lysine, analogously to glucose, is included wherever the term fructose-lysine is mentioned in this description, as is the condensation product of all other sugars, whether naturally-occurring or not.
  • fructose-lysine residues and sugars involves multiple reaction steps. The final steps in this reaction sequence involve the crosslinking of proteins and the production of multimeric species, known as AGE-proteins, some of which are fluorescent. Proteolytic digestion of such modified proteins does not yield lysine covalently linked to a sugar molecule. Thus, these species are not included within the meaning of "fructose-lysine", as that term is used herein. 3.
  • Fructose-lysine-3-phosphate - This compound is formed by the enzymatic transfer of a high e ergy phosphate group from ATP to FL.
  • FL3P fructose-lysine-3 -phosphate
  • FL3P fructose-lysine-3 -phosphate
  • Fructose-lysine-3-phosphate kinase - This term refers to one or more proteins which can enzymatically convert FL to FL3P, as defined above, when additionally supplied with a source of high energy phosphate.
  • (3DG) is the l,2-dicarbonyl-3-deoxysugar (also known as 3-deoxyhexulosone) which is formed upon breakdown of FL3P to yield free lysine and inorganic phosphate.
  • 3-deoxyglucosone is intended to include all possible dicarbonyl sugars which are formed upon breakdown of FL3P, having the broad definition of FL3P stated above.
  • FL3P Lysine Recovery Pathway A lysine recovery pathway exists in human kidney, and possibly other tissues, which regenerates unmodified lysine as a free amino acid or inco ⁇ orated in a polypeptide chain. As explained below, the metabolites produced by this pathway induce a susceptibility to carcinoma.
  • Early glycosylation product(s) This term is intended to encompass any and all early glycosylation products with which the compounds described below are capable of reacting, including, without limitation, early glycosylation products with carbonyl moieties that are involved in the formation of advanced glycosylation end products and that are bound by interaction with the compounds described below. Such products may comprise reactive carbonyl moieties of Amadori products or their further condensation, dehydration and/or rearrangement products, which may condense to form advanced glycosylation end products.
  • reactive carbonyl compounds containing one or more carbonyl moieties (such as glycoladehyde, glyceraldehyde or 3DG) may form from the cleavage of Amadori or other glycosylation end products, and by subsequent reactions with an amine or Amadori products, may form carbonyl-containing advanced glycosylation products such as alkylformyl-glycosylpyrroles.
  • carbonyl moieties such as glycoladehyde, glyceraldehyde or 3DG
  • test animal As used herein this expression refers a strain of laboratory animals which, due to the presence of certain genetic mutations have a higher propensity towards malignant transformation and tumor formation.
  • the Eker rat which has a mutation in the tuberous sclerous gene
  • Tsc-2 is one example of such a susceptible test animal.
  • One of ordinary skill in the art is no doubt aware of a variety of other laboratory rat or mouse strains with increased propensity for tumor formation.
  • the phrase "similar susceptible test animal” refers to animals of a comparable genetic background which are used as control, untreated animals.
  • the present invention evolved from the discovery of a previously unknown metabolic pathway, referred to herein as the FL3P lysine recovery pathway, which produces 3DG in an enzyme-catalyzed reaction.
  • This enzymatic pathway is capable of enzymatic inhibition, thereby reducing the production of toxic 3 DG.
  • 3DG, lysine and inorganic phosphate This reaction also occurs in vivo. It is not currently know if the degradation of FL3P that occurs in vivo is a spontaneous or enzyme catalyzed reaction. It is strongly suspected, however, that enzymatic catalysis is involved, as the production of 3DG from fructose- lysine occurs very rapidly in intact kidney.
  • Figure 1 illustrates the FL3P lysine recovery pathway using the most prevalent glycated-lysine, i.e., fructose-lysine, it will be readily apparent to those skilled in the art that a wide variety of similar molecules can flux through this pathway. Indeed, the substrate selectivity of the FL3P lysine recovery pathway is quite broad, thus warranting the broad definition of the terms given above.
  • lysine recovery pathway is found in a wide variety of warm-blood vertebrate species, including sheep, pig, dog, rabbit, cow, mice and chicken. This pathway is also present in humans. See, WO 98/33492, supra.
  • the ubiquitous presence of the FL3P lysine recovery pathway can be understood, given that lysine is an essential amino acid which is present in relatively low concentrations in most foods.
  • lysine residues in food will exist in the glycated form and the proportion of this modified lysine will increase when the food is cooked. Since these glycated lysine residues can not be utilized for protein synthesis, a recovery pathway for lysine is of great utility and affords a selective advantage to organisms which possess it.
  • a method of reducing susceptibility to tumor formation in a patient associated with the intake of glycated protein is the subject of related U.S. Application No. 09/182J 14, filed October 28, 1998, the entire disclosure of which is inco ⁇ orated by reference in the present specification as though set forth herein in full. That method comprises the administration of a pharmaceutical composition which contains an active compound having inhibitory activity for the enzymatic conversion of fructose-lysine to FL3P.
  • Another aspect of that invention concerns a method of preventing or delaying the onset of tumor formation caused by the formation of AGE-proteins, which comprises administering a therapeutic amount of an agent that inhibits production of 3DG.
  • Another approach entails binding of substrates that function as precursors of 3DG, for example, FL or analogous compounds that are metabolized in vivo to form 3DG.
  • This method is preferably carried out using an immunoreactive agent that specifically binds 3DG precursors in vivo.
  • immunoreactive agents include the monoclonal antibody produced by cell line ATCC HB 9596, which specifically binds an epitope present on glycated albumin.
  • Substrates which may be bound in this manner so as to interfere with the production of 3DG include any of the phosphorylated fructose-lysine moieties, whether free or protein-bound, that can be enzymatically produced in the system of a subject undergoing treatment.
  • Antibodies may be generated, using well-known procedures, to a variety of substrates that may vary by size, including, without limitation, amino acid- fragments, peptide-lysine fragments, polypeptide fragments, and the like.
  • the agents involved in the lysine recovery pathway have been identified in other tissues besides kidney, specifically red blood cells, lens, and peripheral nerve tissues. These agents are also found in pancreas tissue.
  • R, and R 2 are independently hydrogen, lower alkyl, lower alkoxy or an aiyl group; or together with the nitrogen atom form a heterocyclic ring containing from 1 to l heteroatoms and 2 to 6 carbon atoms, the second of said heteroatoms being selected from the group consisting of nitrogen, oxygen and sulfur; and their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups in the compounds of Formula (I) contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof.
  • the lower alkoxy groups have 1 - 6 carbon atoms and include methoxy, ethoxy, propoxy, butoxy, penthyloxy, hexyloxy and branched chain isomers thereof.
  • the aryl groups include both substituted and unsubstituted phenyl and pyridyl groups. Typical aryl group substituents are those such as lower alkyl groups, fluoro, chloro, bromo and iodo atoms.
  • R 2 is preferably hydrogen or an aryl group.
  • R, and R 2 are both alkyl groups, then the compounds having identical R, and R 2 alkyl groups are preferable.
  • R, and R 2 together with the nitrogen atom form a heterocyclic ring containing from 1 to 2 heteroatoms, said heteroatoms being selected from the group consisting of nitrogen, oxygen and sulfur, the preferred heterocyclic rings will be mo ⁇ holino, piperazinyl, piperidinyl and thiomo ⁇ holino, with the mo ⁇ holino being most preferred.
  • N,N-dimethylimidodicarbonimidic diamide imidodicarbonimidic diamide
  • N,N-dipropylimidodicarbonimidic diamide N,N-diethylimidodicarbonimidic diamide; and the pharmaceutically acceptable acid addition salts thereof;
  • Z is N or CH--;
  • X, Y and Q are each independently a hydrogen, amino, heterocyclo, amino lower alkyl, lower alkyl or hydroxy group;
  • R 3 is hydrogen or an amino group; and their corresponding 3-oxides; an their biocompatible and pharmaceutically acceptable salts.
  • the lower alkyl groups of the compounds of formula II contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof.
  • the heterocycylic groups of the compounds of formula II contain from 3-6 carbon atoms and are exemplified by groups such as pyrrolidinyl, 2-methylpyrrolidinyl, piperidinol, 2-methylpiperidino mo ⁇ holino, and hexamethyleneamino.
  • the "floating" X, Y, Q and NHR 3 bonds in Formula II indicate that these variants can be attached to the ring structure at any available carbon juncture.
  • the hydroxy variant of X, Y and Q can also be present on a nitrogen atom.
  • R 4 is hydrogen or acyl
  • R 5 is hydrogen or lower alkyl
  • X a is a substituent selected from the group consisting of lower alkyl, carboxy, carboxymethyl, or a phenyl or pyridyl group, optionally substituted by halogen, lower alkyl, hydroxy lower alkyl, hydroxy, or acetylamino with the proviso that when X is a phenyl or pyridyl group, optionally substituted, then R 2 is hydrogen; and their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups in the compounds of Formula III contain 1 -6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof.
  • the halo variants can be fluoro, chloro, bromo or iodo substituents.
  • salts thereof can be derived from a variety of organic and inorganic acids including but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • R 4 is preferably a methyl group and X a is preferably a phenyl or substituted phenyl group.
  • R ⁇ is hydrogen or a lower alkyl group, or a phenyl group, optionally substituted by 1-3 halo, amino, hydroxy or lower alkyl groups
  • R 7 is hydrogen, a lower alkyl group, or an amino group
  • R 8 is hydrogen or a lower alkyl group; their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups in the compounds of Formula IV contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof.
  • the halo variants can be fluoro, chloro, bromo or iodo substituents. Where the phenyl ring is substituted, the point or points of substitution may be ortho meta or para to the point of attachment of the phenyl ring to the straight chain of the molecule.
  • salts thereof can be derived from a variety of organic and inorganic acids including but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • R ⁇ is preferably a methyl or ethyl group.
  • Representative of the compound of Formula IV are: ethanimidic acid hydrazide; ethanehydrazonic acid hydrazide; N-methylethanimidic acid hydrazide; ethanimidic acid 1-methylhydrazide; formamidrazone (methaniidic acid hydrazide); propanimidic acid hydrazide; benzimidic acid, hydrazide; benzimidic acid, 1-methylhydrazide; propanehydrazonic acid nydrazide; n-butanehydrazonic acid hydrazide;
  • R, and R l0 are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; with the proviso that the "floating" amino group is adjacent to the fixed amino group; their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups of the compounds of Formula V contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof.
  • the lower alkoxy groups of the compounds of formula V contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy, butoxy pentoxy, Le oxy, and the corresponding branched chain isomers thereof.
  • salts thereof can be derived from a variety of organic and inorganic acids including but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • R 10 is preferably also hydrogen.
  • Representative of the compounds of Formula V are: 3 ,4-diaminopyridine; 2,3-diaminopyridine; 5-methyl-2,3-diaminopyridine; 4-methyl-2,3-diaminopyridine;
  • 6-methoxy-2,3 -pyridinediamine 6-methoxy-2,3 -pyridinediamine; and the biocompatible and pharmaceutically acceptable salts thereof;
  • n 1 or 2;
  • R is an amino group or a hydroxyethyl group
  • R ⁇ 2 is an amino, a hydroxyalkylamino, a lower alkyl group or a group of the formula alk-Y a wherein alk is a lower alkylene group and Y a is selected from the group consisting of hydroxy, lower alkoxy, lower alkylthio, lower alkylamino and heterocyclic groups containing 4-7 ring members and 1-3 heteroatoms; with the proviso that when R n is a hydroxyethyl group then R 12 is an amino group; their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl, lower alkylene and lower alkoxy groups refe ⁇ ed to herein contain 1 -6 carbon atoms and include methyl, methylene, methoxy, ethyl, ethylene, ethoxy, propyl, propylene, propoxy, butyl, butylene, butoxy, pentyl, pentylene, pentyloxy, hexyl, hexylene, hexyloxy and the co ⁇ esponding branched chain isomers thereof.
  • the heterocyclic groups refe ⁇ ed to herein include 4-7 membered rings having at least one and up to 3 heteroatoms therein.
  • heterocyclic groups are those such as mo ⁇ holino, piperidino, piperazino, methylpiperazino, and hexamethylenimino.
  • Equivalent to the compounds of Formula I for the pu ⁇ ose of this invention are the biocompatible and pharmaceutically acceptable salts thereof.
  • Such salts can be derived from a variety of organic and inorganic acids including but not limited to, methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • substituents are prefe ⁇ ed. For instance, when R, , is a hydroxyethyl group, then R 12 is an amino group.
  • R I2 is preferably a hydroxy lower alkylamino, a lower alkyl group or a group of the formula alk-Y, wherein alk is a lower alkylene group and Y is selected from the group consisting of hydroxy, lower alkoxy, lower alkylthio, lower alkylamino and heterocyclic groups containing 4-7 ring members and 1-3 heteroatoms.
  • Representative of the compounds of Formula VI are: l-amino-2-[2-(2-hydroxyethyl)hydrazino]-2-imidazoline; l-amino-2-(2-hydroxyethylamino)-2-imidazoline; 1 -(2-hydroxyethyl)-2-hydrazino- 1 ,4,5,6-tetrahydropyrimidine;
  • R 13 is a hydrogen or an amino group
  • R, 4 and R, 5 are independently an amino group, a hydrazino group, a lower alkyl group, or an aryl group; with the proviso that one of R 13 , R 14 and R 15 must be an amino or a hydrazino group; and their biologically or pharmaceutically acceptable acid or alkali addition salts.
  • the lower alkyl groups refe ⁇ ed to above preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the aryl groups encompassed by the Formula VII are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g. tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy or lower alkoxy groups.
  • the halo atoms in the Formula VII may be fluoro, chloro, bromo or iodo.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
  • R 13 is hydrogen
  • R 14 is preferably an amino group
  • R ]4 is a hydrazino group
  • R is preferably an amino group
  • Representative of the compounds of Formula VII are: 3 ,5-diamino- 1 ,2,4-triazole; 3-methyl-5-amino-l,2,4-triazole; 4-amino-3-hydrazino-5-methyl- 1 ,2,4-triazole; 3,4-diamino-5-methyl-l,2,4-triazole;
  • R 16 is hydrogen or an amino group
  • R 17 is an amino group or a guanidino group when R 16 is hydrogen
  • R 17 is an amino group when R 16 is an amino group
  • R 18 and R I9 are independently hydrogen, hydroxy, a lower alkyl group, a lower alkoxy group, or an aryl group; and their biologically or pharmaceutically acceptable acid or alkali addition salts.
  • the lower alkyl groups in the compounds of Formula VIII preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched chain isomers thereof.
  • the lower alkoxy groups likewise contain 1-6, and preferably 1-3, carbon atoms, and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • aryl groups encompassed by the above formula are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy or lower alkoxy groups.
  • the halo atoms in the above Formula VIII may be fluoro, chloro, bromo or iodo.
  • the biologically or pharmaceutically acceptable salts of the compounds of Formula VIII are those tolerated by the mammalian body and include acid addition salts derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
  • R 20 is selected from the group consisting of hydrogen; lower alkyl, optionally substituted by one or two hydroxyl, thiol, phenyl, hydroxyphenyl, lower alkylthiol, carboxy, aminocarboxy or amino groups and R 21 is selected from the group of hydrogen and an acyl group; and their biocompatible and pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups of the compounds of Formula IX contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl and the co ⁇ esponding branched chain isomers thereof.
  • the acyl groups refe ⁇ ed to herein are residues of lower alkyl, aryl and heteroaryl carboxylic acids containing 2-10 carbon atoms. They are typified by acetyl, propionyl, butanoyl, valeryl, hexanoyl and the co ⁇ esponding higher chain and branched chain analogs thereof.
  • the acyl radicals may also contain one or more double bonds and/or an additional acid functional group e.g., glutaryl or succinyl.
  • amino acids utilized herein can possess either the L&D; stereochemical configuration or be utilized as mixtures thereof. However, the L-configuration is prefe ⁇ ed.
  • salts thereof can be derived from a variety of inorganic and organic acids such as methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic, phosphoric and related acids.
  • Representative compounds of the compounds of Formula IX are: lysine; 2,3-diaminosuccinic acid; cysteine and the biocompatible and pharmaceutically acceptable salts thereof.
  • R 22 and R 23 are independently hydrogen, an amino group or a mono- or di-amino lower alkyl group
  • R 24 and R 25 are independently hydrogen, a lower alkyl group, an aryl group
  • or an acyl group with the proviso one of R 22 and R 23 must be an amino group or an mono- or diamino lower alkyl group; and their biologically or pharmaceutically acceptable acid or alkali addition salts.
  • the lower alkyl groups of the compounds of Formula X contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the mono-or di-amino alkyl groups are lower alkyl groups substituted in the chain by one or two amino groups.
  • the aryl groups refe ⁇ ed to herein encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups.
  • the acyl groups refe ⁇ ed to herein are residues of lower alkyl, aryl and heteroaryl carboxylic acids containing 2-10 carbon atoms. They are typified by acetyl, propionyl, butanoyl, valeryl, hexanoyl and the co ⁇ esponding higher chain and branched chain analogs thereof.
  • the acyl radicals may also contain one or more double bonds and/or an additional acid functional group, e.g., glutaryl or succinyl.
  • heteroaryl groups refe ⁇ ed to above encompass aromatic heterocyclic groups containing 3-6 carbon atoms and one or more heteroatoms such as oxygen, nitrogen or sulfur.
  • the halo atoms in the above Formula X may be fluoro, chloro, bromo and iodo.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, propoxy, isopropoxy and the like.
  • biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by acid addition salts derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, glucomic, ascorbic and related acids.
  • organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, glucomic, ascorbic and related acids.
  • substituents are prefe ⁇ ed. For instance, when R 22 and R 23 are both amino groups, then R 24 and R 25 are preferably both hydrogen atoms.
  • R 22 or R 23 is amino group and one of R 24 or R 25 is an aryl group, the other of R 24 and R 25 is preferably hydrogen.
  • Representative compounds of Formula X are:
  • 2-aminoimidazole 4-(2,4-dichlorophenyl)-2-aminoimidazole; -(4-methoxyphenyl)-2-aminoimidazole; -(4-ethoxyphenyl)-2-aminoimidazole; -(4-fluorophenyl)-2-aminoimidazole; -(4-bromophenyl)-2-aminoimidazole; -butyl-2-aminoimidazole; -ethyl-2-aminoimidazole; -methyl-2-aminoimidazole; -phenyl-2-aminoimidazole; -propyl-2-aminoimidazole; 1 -(3 -aminopropyl)imidazole;
  • R 26 is a hydroxy, lower alkoxy, amino, amino lower alkoxy, mono-lower alkylamino lower alkoxy, di-lower alkylamino lower alkoxy or hydrazino group, or a group of the formula ⁇ NR 29 R 30 , wherein R 29 is hydrogen or lower alkyl, and R 30 is an alkyl group of 1-20 carbon atoms, an aryl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, cycloloweralkyl group or a heterocyclic group containing 4-7 ring members and 1-3 heteroatoms; or R 29 and R 30 together with the nitrogen form a mo ⁇ holino, piperidinyl, or piperazinyl group; or when R 29 is hydrogen, then R 30 can also be a hydroxy group;
  • R 27 is 0-3 amino or nitro groups, and/or a hydrazino group, a hydrazinosulfonyl group, a hydroxyethylamino or an amidino group;
  • R 2g is hydrogen or one or two fluoro, hydroxy, lower alkoxy, carboxy, loweralkylamino, dilower alkylamino or a hydroxyloweralkylamino groups; with the proviso that when R 26 is hydroxy or lower alkoxy, then R 27 is a non-hydrogen substituent; with the further proviso that when R 26 is hydrazino, then there must be at least two non-hydrogen substituents on the phenyl ring; and with the further proviso that when R 2g is hydrogen, then R 30 can also be an aminoimino, guanidyl, aminoguanidinyl or diaminoguanidyl group; their pharmaceutically acceptable salts and hydrates.
  • the lower alkyl groups of the compounds of Formula XI contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the cycloalkyl groups contain 4-7 carbon atoms and are exemplified by groups such as cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl and cycloheptyl groups.
  • heterocyclic groups of the compounds of Formula XI include 4-7 membered rings having at least one and up to 3 heteroatoms, e.g., oxygen, nitrogen, or sulfur, therein, and including various degrees of unsaturation.
  • Representatives of such heterocyclic groups are those such as mo ⁇ holino, piperidino, homopiperidino, piperazino, methylpiperazino, hexamethylenimino, pyridyl, methylpyridyl, imidazolyl, py ⁇ olidinyl, 2,6-dimethylmo ⁇ holino, furfural, 1,2,4-triazoylyl, thiazolyl, thiazolinyl, methylthiazolyl, and the like.
  • salts and hydrates thereof are the biocompatible and pharmaceutically acceptable salts and hydrates thereof.
  • Such salts can be derived from a variety of organic and inorganic acids, including, but not limited to, methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids When the compounds of Formula XI contain one or more asymmetric carbon atoms, mixtures of enantiomers, as well as the pure (R) or (S) enantiomeric form can be utilized in the practice of this invention.
  • R 2 is preferably one or two amino groups, or a single hydrazino or a single hydrazino-sulfonyl group.
  • R 2 is preferably para to the carboxy substituent.
  • R is hydroxy and R 2 is two amino groups, they are preferably meta and para to the carboxy substituent.
  • R 2 is preferably meta to the carboxy substituent.
  • R 2 is preferably a single amino group.
  • R 2 is preferably a single amino group.
  • Representative compounds of the present invention are: -(cyclohexylamino-carbonyl)-o-phenylene diamine hydrochloride; -aminobenzhydrazide; ,4-diaminobenzhy drazide; -(n-butylamino-carbonyl)-o-phenylene-diamine dihydrochloride; -(ethylamino-carbonyl)-o-phenylene-diamine dihydrochloride; -carbamoyl-o-phenyiene diamine hydrochloride; -hydroxybenzhydrazide; -amino-4-hydroxybenzoic acid; -amino-3-hydroxybenzoic acid; -amino-4-hydroxybenzhy drazide; -amino-4-hydroxybenzhy drazide dihydrochloride; -amidinobenzarnide hydrochloride; -(mo ⁇ holino-carbonyl)-o-phenylene-d
  • 4,5-difluoroanthranilic acid 4-fluoro-3-nitrobenzoic acid; 3-amino-2,5,6-trifluorobenzoic acid; 2-fluoro-5-nitrobenzoic acid; methyl 3,5-diamino-4-hydroxy benzoate; 3-amino-5-nitrosalicylic acid; 2,4-dihydroxy-3,5-dinitrobenzoic acid; 3,5-dinitro-4-hydroxybenzoic acid; methyl 3 ,5 -dinitro-4-hydroxybenzoate; ethyl 3,5-dinitro-4-hydroxybenzoate; 3,5-dinitro-p-toluic acid;
  • R 31 is hydrogen, a lower alkyl or hydroxy group
  • R 32 is hydrogen, hydroxy lower alkyl, a lower alkoxy group, a lower alkyl group, or an aryl group
  • R 33 is hydrogen or an amino group
  • the lower alkyl groups of the compounds of Formula XII contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and include methoxy, ethoxy, isopropoxy, propoxy and the like.
  • the hydroxy lower alkyl groups include primary, secondary and tertiary alcohol substituent patterns.
  • aryl groups of the compounds of Formula XII encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups.
  • halo atoms in the above Formula XII may be fluoro, chloro, bromo and iodo.
  • biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by acid addition salts derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
  • organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
  • X b is oxygen or nitrogen;
  • R 34 is hydrogen, lower alkyl or aryl;
  • R 35 is hydrogen, lower alkyl, lower alkenyl, aryl, or hydroxy lower alkyl;
  • R 36 is hydrogen, hydroxy, lower alkyl, aryl, halo, lower alkanoyl, or aryl lower alkyl; and their biologically or pharmaceutically acceptable salts with organic or inorganic bases.
  • the lower alkyl groups of the compounds of Formula XIII contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the lower alkenyl groups refe ⁇ ed to contain 2-6 carbon atoms and include ethenyl, propenyl and the like.
  • the lower alkanoyl groups likewise contain 2-6 carbon atoms and are exemplified by acetyl, propionyl and the like.
  • the aryl groups of the compounds of Formula XIII encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups.
  • the halo atoms in the above in Formula XIII may be fluoro, chloro, bromo and iodo.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, propoxy, isopropoxy and the like.
  • biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by salts derived from a variety of organic and inorganic bases such as amines, e.g., procaine, or N,N'-dibenzylethylenediamine, or alkali or alkaline-earth metal salts, e.g., potassium or sodium hydroxide, calcium hydroxide, and the like.
  • amines e.g., procaine, or N,N'-dibenzylethylenediamine
  • alkali or alkaline-earth metal salts e.g., potassium or sodium hydroxide, calcium hydroxide, and the like.
  • alkali or alkaline-earth metal salts e.g., potassium or sodium hydroxide, calcium hydroxide, and the like.
  • R 34 and R 35 are preferably hydrogen, lower alkyl or phenyl. Also prefe ⁇ ed are the compounds wherein R 34 , R 35 and R 36 are all hydrogen, or those wherein R 36 is hydrogen.
  • Representative of the compounds of Formula XIII are: 2,4-py ⁇ olidinedione;
  • 2,4(3H,5H)-furandione (tetronic acid); 5-ethyl-2,4(3H,5H)-furandione; 5-methyl-2,4(3H,5H)-furandione; 5 -propy 1-2,4(3 H,5H)-furandione; 5,5-dimethyl-2,4(3H,5H)-furandione;
  • R 37 is a lower alkyl group, or a group of the iOrmula-NR 4) R 42 wherein R 41 is hydrogen, and R 42 is a lower alkyl group or a hydroxy(lower)alkyl group; or R 41 and R 42 together with the nitrogen atom are a heterocyclic group containing 4-6 carbon atoms and, in addition to the nitrogen atom, 0-1 oxygen, nitrogen or sulfur atoms;
  • R 3g is hydrogen or an amino group
  • R 39 is hydrogen or an amino group
  • R 40 is hydrogen or a lower alkyl group; with the proviso that at least one of R 38 , R 39 , and R 40 is other than hydrogen; and with the further proviso that R 37 and R 38 cannot both be amino groups; their pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups of the compounds of Formula XIV contain
  • the heterocyclic groups formed by the N-R 41 R 42 group are 4-7 membered rings having at 0-1 additional heteroatoms, e.g., oxygen, nitrogen, or sulfur, therein, and including various degrees of unsaturation.
  • Representatives of such heterocyclic groups are those such as mo ⁇ holino, piperidino, hexahydroazepino, piperazino, methylpiperazino, hexamethylenimino, pyridyl, methylpyridyl, imidazolyl, py ⁇ olidinyl, 2,6-dimethylmo ⁇ holino, 1,2,4-triazoylyl, thiazolyl, thiazolinyl, and the like.
  • salts thereof can be derived from a variety of organic and inorganic acids, including, but not limited to, methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
  • methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids When the compounds of Formula XIV contain one or more asymmetric carbon atoms, mixtures of enantiomers, as well as the pure (R) or (S) enantiomeric form can be utilized in the practice of this invention.
  • N-(4-mo ⁇ holino)hydrazinecarboximidamide 1 -methyl-N-(4-mo ⁇ holino)hydrazinecarboximidamide; l-methyl-N-(4-piperidino)hydrazinecarboximidamide; l-(N-hexahydroazepino)hydrazinecarboximidamide;
  • R 46 is hydrogen, lower alkyl or a water-solubilizing ester moiety
  • W is a carbon-carbon bond or an alkylene group of 1-3 carbon atoms
  • R 44 is a lower alkyl, aryl, or heteroaryl group
  • R 45 is hydrogen, a lower alkyl, aryl or heteroaryl group; and their biologically or pharmaceutically acceptable acid addition salts.
  • the lower alkyl groups of the compounds of Formula XI preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo, hydroxy, amino or lower alkylamino groups.
  • alkylene groups of the compounds of Formula XV likewise can be straight or branched chain, and are thus exemplified by ethylene, propylene, butylene, pentylene, hexylene, and their co ⁇ esponding branched chain isomers.
  • the water solubilizing ester moiety can be selected from a variety of such esters known in the art. Typically, these esters are derived from dialkylene or trialkylene glycols or ethers thereof, dihydroxyalkyl groups, arylalkyl group, e.g., nitrophenylalkyl and pyridylalkyl groups, and carboxylic acid esters and phosphoric acid esters of hydroxy and carboxy-substituted alkyl groups. Particularly prefe ⁇ ed water- solubilizing ester moieties are those derived from 2,3-dihydroxypropane, and 2- hydroxyethylphosphate.
  • aryl groups encompassed by the above Formula XV are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and are optionally substituted by 1-2 halo, nitro, hydroxy or lower alkoxy groups.
  • the position of the substituents may be ortho, meta, or para to the point of attachment of the phenyl or aryl ring to the nitrogen of the hydrazine group.
  • the halo atoms in the above Formula XV may be fluoro, chloro, bromo or iodo.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoy, n-propoxy, isopropoxy and the like.
  • heteroaryl groups in the above Formula XV contain 1-2 heteroatoms, i.e., nitrogen, oxygen or sulfur, and are exemplified by furyl, py ⁇ olinyl, pyridyl, pyrimidinyl, thienyl, quinolyl, and the co ⁇ esponding alkyl substituted compounds.
  • furyl i.e., nitrogen, oxygen or sulfur
  • py ⁇ olinyl pyridyl
  • pyrimidinyl pyrimidinyl
  • thienyl quinolyl
  • co ⁇ esponding alkyl substituted compounds co ⁇ esponding alkyl substituted compounds.
  • Formula XV are the biologically and pharmaceutically acceptable acid addition salts thereof.
  • Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, methanesulfonic and related acids.
  • certain substituents are prefe ⁇ ed. For instance, the compounds wherein W is a carbon-carbon bond, R 44 is a methyl group and R 45 is hydrogen are prefe ⁇ ed.
  • Representative of the compounds of Formula XV are: methyl glyoxal bis-(2-hydrazino-benzoic acid)hydrazone; methyl glyoxal bis-(dimethyl 2-hydrazinobenzoate) hydrazone; methyl glyoxal bis-(phenylhydrazine)hydrazone; methyl glyoxal bis-(dimethyl 2-hydrazinobenzoate) hydrazone; methyl glyoxal bis-(4-hydrazinobenzoic acid)hydrazone; methyl glyoxal bis-(dimethyl 4-hydrazinobenzoate)hydrazone; methyl glyoxal bis-(2-pyridyl)hydrazone; methyl glyoxal bis-(diethylene glycol methyl ether-2-hydrazinobenzoate) hydrazone; methyl glyoxal bis-[ 1 -(2,3-dihydroxypropane)-2-hydr
  • R 53 - C N - NH - C - N - R 48 R 49
  • R 47 and R 4g are each hydrogen or, together, are an alkylene group of 2-3 carbon atoms, or, when R 47 is hydrogen, then R 4g can be a group of the formula
  • alk is a straight or branched chain alkylene group of 1-8 carbon atoms
  • R 50 and R 51 are independently each a lower alkyl group of 1-6 carbon atoms, or together with the nitrogen atom form a mo ⁇ holino, piperdinyl or methylpiperazinyl group
  • R 49 is hydrogen, or when R 47 and R 48 are together an alkylene group of 2-3 carbon atoms, a hydroxyethyl group;
  • W is a carbon-carbon bond or an alkylene group of 1 -3 carbon atoms
  • R 52 is a lower alkyl, aryl, or heteroaryl group and R 53 is hydrogen, a lower alkyl, aryl or heteroaryl group; with the proviso that when W is a carbon-carbon bond, then R 52 and R 53 together can also be a 1,4-butylene group; or W is a 1,2-, 1,3-, or 1 ,4-phenylene group, optionally substituted by one or two lower alkyl or amino groups, a 2,3 -naphthy lene group; a 2,5-thiophenylene group; or a 2,6-pyridylene group; and R 52 and R 53 are both hydrogen or a lower alkyl group; or W is an ethylene group and R 52 and R 53 together are an ethylene group; or W is an ethenylene group and R 52 and R 53 together are an ethenylene group; or W is a m
  • the lower alkyl groups of the compounds of Formula XVI preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo hydroxy, amino or lower alkylamino groups.
  • the alkylene groups of the compounds of Formula XVI likewise can be straight or branched chain, and are thus exemplified by ethylene, propylene, butylene, pentylene, hexylene, and their co ⁇ esponding branched chain isomers.
  • the aryl groups encompassed by the above Formula XVI are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g. tolyl and xylyl, and are optionally substituted by 1-2 halo, hydroxy or lower alkoxy groups.
  • the halo atoms in the above Formula XVI may be fluoro, chloro, bromo or iodo.
  • the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • heteroaryl groups in the above Formula XNI contain 1-2 heteroatoms, i.e. nitrogen, oxygen or sulfur, and are exemplified by be furyl, py ⁇ olinyl, pyridyl, pyrimidinyl, thienyl, quinolyl, and the co ⁇ esponding alkyl substituted compounds.
  • Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, methanesulfonic and related acids.
  • R 54 and R 55 are independently selected from the group consisting of hydrogen, hydroxy(lower) alkyl, lower acyloxy (lower)alkyl, lower alkyl, or R 54 and R 55 together with their ring carbons may be an aromatic fused ring;
  • Z a is hydrogen or an amino group
  • A is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
  • the lower alkyl groups of the compounds of Formula XVII contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the co ⁇ esponding branched-chain isomers thereof.
  • the lower alkynyl groups contain from 2 to 6 carbon atoms.
  • the lower alkoxy groups contain from 1 to 6 carbon atoms, and include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy, and the co ⁇ esponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo, hydroxy, amino or lower alkylamino groups.
  • the lower acyloxy(lower)alkyl groups encompassed by the above Formula XVII include those wherein the acyloxy portion contain from 2 to 6 carbon atoms and the lower alkyl portion contains from 1 to 6 carbon atoms.
  • Typical acyloxy portions are those such as acetoxy or ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, and the co ⁇ esponding branched chain isomers thereof.
  • Typical lower alkyl portions are as described hereinabove.
  • aryl groups encompassed by the above formula are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and are optionally substituted by 1-2 halo, hydroxy, lower alkoxy or di(lower)alkylamino groups.
  • Prefe ⁇ ed aryl groups are phenyl, methoxyphenyt and 4-bromophenyl groups.
  • halo atoms in the above Formula XVII may be fluoro, chloro, bromo or iodo.
  • the compounds of Formula XVII are formed as biologically and pharmaceutically acceptable salts.
  • Useful salt forms are the halides, particularly the bromide and chloride, tosylate, methanesulfonate, and mesitylenesulfonate salts.
  • Other related salts can be formed using similarly non-toxic, and biologically and pharmaceutically acceptable anions.
  • Representative of the compounds of Formula XVII are: -amino thiazolium mesitylenesulfonate; -amino-4,5-dimethylaminothiazolium mesitylenesulfonate; ,3-diaminothiazolinium mesitylenesulfonate; -(2-methoxy-2-oxoethyl)-thiazolium bromide; -(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide; -(2-methoxy-2-oxoethyl)-4-methylthiazolium bromide; -(2-phenyl-2-oxoethyl)-4-methylthizolium bromide; -(2-pheny 1-2-oxoethy l)-4,5-dimethylthiazolium bromide; -amino-4-methy lthiazolium mesitylenesulfonate ;
  • Rg, and R ⁇ are each independently selected from the group consisting of hydrogen; C,. 10 alkyl, straight or branched chain; aryl C alkyl; and mono- or disubstituted aryl C M alkyl where the substituents are fluoro, chloro, bromo, iodo or C,.- 0 alkyl, straight or branched chain;
  • R S8 and R 59 are each independently selected from the group consisting of hydrogen, amino, and mono- or di-substituted amino where the substituents are C,. 10 alkyl, straight or branched chain C 3 . 8 , cycloalkyl; provided that R, and R 2 may not both be amino or substituted amino; and
  • R 60 is hydrogen, trifluoromethyl; fluoro; chloro; bromo; or iodo; or a pharmaceutically acceptable salt thereof.
  • the compounds to be used in the methods of this invention also include so-called nutraceuticals, for example, certain amino acids, vitamins or the like which are effective when administered individually, but preferably in combination, to bind to or otherwise interfere with the production of 3DG.
  • nutraceuticals for example, certain amino acids, vitamins or the like which are effective when administered individually, but preferably in combination, to bind to or otherwise interfere with the production of 3DG.
  • Representative examples of such substances are Vitamin C and lysine.
  • the methods of the present invention may also be practiced using antibodies or other immunoreactive substances that are capable of binding to 3DG precursors. These include, without limitation, the antibodies described in the above-mentioned U.S. Patents Nos. 5,223,392, 5,494,791 and 5,518,720.
  • ingredients may be prepared in various forms for administration, including both liquids and solids.
  • the preparation may be in the form of tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles.
  • pharmaceutically acceptable ca ⁇ ier medium includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • ca ⁇ ier media include gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or the like.
  • Remington's Pharmaceutical Sciences. Fifteenth Edition, E.W. Martin (Mack Publishing Co., Easton, PA 1975) discloses various ca ⁇ iers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the enzyme inhibitors of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical preparation, its use is contemplated to be within the scope of this invention.
  • the active agent(s) may be present in an amount of at least 0.01% and generally not more than
  • the proportion of active agent varies between 1.0% - 5.0% by weight of the composition.
  • Anti-hypertensive drugs including particularly the angiotensin- converting enzyme (ACE) inhibitors, may also be included as supplementary active agents in the pharmaceutical preparations of this invention.
  • ACE angiotensin- converting enzyme
  • auxiliary agents such as compounds that will protect the active agent from acid destruction in the stomach or facilitate the abso ⁇ tion of the active compound into the bloodstream can also be inco ⁇ orated into the pharmaceutical preparation, if necessary or desirable.
  • auxiliary agents may include, for example, complexing agents such as borate or other salts which partially offset the acid conditions in the stomach, and the like. Abso ⁇ tion can be increased by delivering the active compound as the salt of a fatty acid (in those cases where the active compound contains one or more basic functional groups).
  • the compounds of the invention, along with any supplementary active ingredient(s) may be administered, using any amount and any route of administration effective for binding to glycated protein, in vivo.
  • the expression "therapeutically effective amount”, as used herein, refers to an amount of the therapeutic agent which is at once non-toxic and sufficient to provide the desired reduction in susceptibility to carcinoma associated with the intake of glycated protein.
  • the exact amount required may vary, depending on the species, age, and general condition of the patient, the particular therapeutic agent and its mode of administration, and the like.
  • agents used in the method of the invention are preferably formulated in dosage form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to a physically discrete unit of the therapeutic agent appropriate for the patient to be treated. Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical ca ⁇ ier medium. Typically, the small molecule agents used in practicing this invention will be administered in dosage units containing from about 25 mg to about 2500 mg of the compound, per dose, with a range of about 250 mg to about 750 mg being prefe ⁇ ed.
  • the agents of the invention may be administered orally, parenterally, such as by intramuscular injection, intraperitoneal injection, intravenous infusion or the like, depending on the stability of the selected compounds to the various physiological conditions encounted in each route of administration.
  • the small molecule agents may be administered orally or parenterally at dosage levels of about 1 mg to about 50 mg and preferably from about 10 mg to about 25 mg/kg, of patient body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Orally active agents are particularly prefe ⁇ ed, provided the oral dose is capable of generating blood and/or target tissue levels of the above- described agents that are therapeutically active.
  • the normal concentration of immunoreactive agent used in the methods of this invention will be from about 1.0 mg and about 10 mg. These will typically be administered by intravenous or intraarterial infusion.
  • the compounds of the invention will typically be administered once per day or up to four times per day, depending upon the specific agent chosen.
  • the exact regimen for administration of the compounds described herein will necessarily be dependent on the needs of the individual subject undergoing treatment, the type of therapy administered and the judgment of the attending physician.
  • the term "subject" includes both humans and animals.
  • 3DG is an endogenously produced reactive dicarbonyl co ⁇ elated with numerous pathologic conditions
  • 3DG is present in various foodstuffs, the ingestion of which contributes to endogenous levels of 3DG.
  • Examples of a number of commercial 3DG-containing syrups and a soft drink, along with the 3DG content thereof is presented in the following table.
  • High Fructose Corn Syrup #1 2.65 ⁇ mols/g High Fructose Corn Syrup #2 2.26 ⁇ mols/g Karo® Pancake Syrup 380 nmols/g Karo® Light Syrup 340 nmols/g Crystal Light Syrup (Acme) 57 nmols/g Aunt Jemima® Pancake Syrup 360 nmols/g Pepsi Cola® 0.54 mM
  • xylose isomerase The production of high fructose corn syrup involves treating a solution of glucose with xylose isomerase. 3DG is produced as a by-product of this process. Furthermore, while catalyzing the reversible interconversion of D- xylose and D-xylulose, xylose isomerase (XI) has been observed by 13C-NMR spectroscopy to produce D-lyxose and 3-deoxy-D-xylosone (3-deoxy-D-glycero- pentose-2-ulose).
  • High fructose corn syrup solutions having reduced 3DG content may be obtained by treatment with an adsorbent resin or other suitable separation medium capable of selectively binding 3DG.
  • Another detoxification reaction oxidizes 3DG to 3-deoxy-2-ketogluconic acid (DGA_ by oxoaldehyde dehydrogenase (Fujii et al., Biochem. Biophys. Res. Comm.. 210: 852 (1995)).
  • exogenous 3DG found in foodstuffs therefore represents an additional risk factor for the development and progression of complications in diabetic patients. Even in a clinically healthy individual, sufficient amounts of 3DG may exceed the physiologic capacity for detoxification. Thus, consumption of exogenous 3DG in foodstuffs is a risk factor for healthy individuals for the development of 3DG- related diseases and conditions.
  • glycated protein diet was fed a glycated protein diet: the other cohort was on a control diet.
  • the glycated protein diet consisted of a standard nutritious diet to which 3% glycated protein had been added.
  • the glycated protein was made by mixing together casein and glucose (2:1) adding water (2X the weight of the dried material) and baking the mixture at 60°C for 72 hours.
  • the control was prepared in the same way except that no water was used and the casein and glucose were not mixed prior to baking.
  • Rats were placed on the diets imme ⁇ i «tely following weaning at three weeks of age and maintained on the diets ad libitum for the next 16 weeks. The animals were then sacrificed, the kidneys fixed and nemotoxylin and eosin sections were made. These were examined for lesions by a trained pathologist. Four types of lesions were identified. These included: cysts, very small collections of tumor-like cells, typically less than 10 cells; small tumors, 0.5 mm or less, and tumors greater than 0.5 mm. For every type, more lesions were observed in the animals on the glycated diet than on the control diet as shown in the following table.
  • the average number of lesions per kidney section was computed for each diet. These were 0.82 ⁇ 0.74 and 2.43 ⁇ 2.33 in the control and glycated diet, respectively. The likelihood of this happening by chance is about 2 in 100,000.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés d'utilisation de plusieurs composés capables de lier la 3-désoxyglocosone (3DG) ou les précurseurs de cette substance, de manière à réduire une prédisposition à la formation de tumeurs et/ou à prévenir ou retarder l'apparition de tumeurs provoquées par la 3DG et ses précurseurs. L'invention concerne également la réduction de 3DG dans du sirop de maïs enrichi en fructose, de manière que le sirop de maïs enrichi en fructose provoque moins facilement des formations de tumeurs.
EP00923361A 1999-04-15 2000-04-17 Procede destine a reduire la predisposition a la formation de tumeurs provoquees par la 3-desoxyglucosone et les precurseurs de cette substance Withdrawn EP1175155A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12941599P 1999-04-15 1999-04-15
US129415P 1999-04-15
PCT/US2000/010071 WO2000062626A1 (fr) 1999-04-15 2000-04-17 Procede destine a reduire la predisposition a la formation de tumeurs provoquees par la 3-desoxyglucosone et les precurseurs de cette substance

Publications (2)

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EP1175155A1 EP1175155A1 (fr) 2002-01-30
EP1175155A4 true EP1175155A4 (fr) 2005-10-19

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EP00923361A Withdrawn EP1175155A4 (fr) 1999-04-15 2000-04-17 Procede destine a reduire la predisposition a la formation de tumeurs provoquees par la 3-desoxyglucosone et les precurseurs de cette substance

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EP (1) EP1175155A4 (fr)
AU (1) AU777745B2 (fr)
CA (1) CA2369755A1 (fr)
HK (1) HK1040164A1 (fr)
IL (2) IL145957A0 (fr)
MX (1) MXPA01010489A (fr)
NZ (1) NZ515049A (fr)
WO (1) WO2000062626A1 (fr)

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US6518269B1 (en) 2000-07-28 2003-02-11 University Of Arizona Foundation Cancer treatment
US6290929B1 (en) * 2000-07-28 2001-09-18 The Procter & Gamble Company Cancer treatment
SE523153C2 (sv) * 2000-12-28 2004-03-30 Gambro Lundia Ab Metod för detoxifiering av medicinsk lösning
US7622117B2 (en) 2002-04-17 2009-11-24 Dynamis Therapeutics, Inc. 3-deoxyglucosone and skin
US9051583B2 (en) 2011-12-19 2015-06-09 Northwestern University Modified silica shell particles, and methods of making and using the same
AR108671A1 (es) * 2016-06-03 2018-09-12 Enlibrium Inc Análogos de diamida imidodicarbonimidica

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Also Published As

Publication number Publication date
AU777745B2 (en) 2004-10-28
IL145957A (en) 2007-02-11
IL145957A0 (en) 2002-07-25
WO2000062626A1 (fr) 2000-10-26
HK1040164A1 (zh) 2002-05-31
MXPA01010489A (es) 2002-05-06
CA2369755A1 (fr) 2000-10-26
AU4350100A (en) 2000-11-02
NZ515049A (en) 2004-12-24
EP1175155A1 (fr) 2002-01-30

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